AIMS: The goal of this application is to apply for Research Career Scientist (RCS) Award and to support Dr. Heather Francis? VA research program. NOMINEE: The candidate, Dr. Heather Francis, is the Scientific Director of the inaugural Indiana Center for Liver Research (ICLR) at Richard L. Roudebush VA Medical Center in Indianapolis as well as a full Professor of Medicine in the Department of Internal Medicine, Division of Gastroenterology and Hepatology at Indiana University. Dr. Francis recently assumed this position in January of 2019 and continues her VA funded work in Indianapolis. Prior to moving to Indiana, Dr. Francis was a Research Biologist at Central Texas Veteran?s Health Care System in Temple, Texas and she has had continuous VA funding since 2012 with the inception of a VA Career Development Award which she transitioned into a BLRD VA Merit Award in 2016. Dr. Francis? area of interest and expertise lies in the pathophysiology of cholangiocyte (bile duct cells) biology and Dr. Francis has been trained and mentored by a world-renowned expert, Dr. Gianfranco Alpini (2007 ? 2015). Dr. Francis has become a leader in the field of hepatic mast cells and their contribution to liver diseases and also how mast cells interact with resident liver cells, including cholangiocytes and hepatic stellate cells. Currently, Dr. Francis holds a BLRD VA Merit (resubmitted and scored, June 2019) and two NIH NIDDK R01 awards (role: PI on both). She serves as a permanent member on the NIH NIDDK Hepatobiliary Pathophysiology Study Section (2018- 2023) and is on the editorial board of Hepatology, Laboratory Investigation and PLoSOne. Dr. Francis has been an active mentor since 2011 and continues to serve on graduate student committees, train post-doctoral fellows and develop collaborations with clinical partners. In addition, since 2012, Dr. Francis has maintained a number of collaborations with VA funded investigators that has resulted in numerous publications. IMPACT: Primary Sclerosing Cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts which normally allow bile to drain from the gallbladder. Patients who suffer from PSC may be asymptomatic or suffer from a myriad of symptoms such as jaundice, itching and abdominal pain. In addition, most patients with PSC (upwards of 75%) also suffer from inflammatory bowel diseases like Ulcerative Colitis, thus complicating their treatment strategies. The risks of PSC include increased incidences of CCA, but also colorectal cancer and gallbladder carcinoma are found in more patients with PSC then without. The causes of PSC are not fully known; however, some studies point to genetic links, malfunctioning immune systems and a dysregulation of the gut microbiota. Treatment options for patients with PSC are severely limited. There is a sub-population of patients who get relief from treatment with the bile acid, ursodeoxycholate; however, not all patients respond. Liver transplantation remains the most definitive ?cure? or treatment for PSC, but there is a chance of recurrence following transplantation. The estimated survival time from diagnosis is ~20 years depending upon the stage of discovery and management throughout. Our work has demonstrated that histamine (derived primarily from mast cells) levels are increased in patients with PSC and patients with CCA. In addition, we have shown that mast cell numbers increase in these patients and are found close to bile ducts, thus making this work highly clinically important. This proposal aims to identify biomarkers and potential novel therapies to both alleviate symptoms and offer curative advances without transplantation. In addition, since PSC can develop into CCA (which is increased in a subpopulation of U.S. Veterans), we will also aim to understand the transition of PSC and signaling mechanisms that regulate this development of CCA.